Insulin signaling is essential for normal glucose homeostasis. Insulin signaling occurs via a cascade of tyrosyl phosphorylation events that are terminated by dephosphorylation through the actions of protein tyrosine phosphatases (PTPs). The expression and activity of specific PTPs is increased in insulin target tissues of obese, insulin resistant humans and rodents. The overall goal is to determine the role of protein tyrosine phosphatase 1B (PTP1B) in insulin target tissues in the regulation of glucose homeostasis, insulin sensitivity and adiposity. Specific aims are: 1) To determine whether overexpression of PTP1B selectively in individual insulin target tissues (muscle, liver or adipose tissue) of transgenic mice results in insulin resistance, glucose intolerance and/or obesity. 2) To determine whether insulin resistance, impaired glucose tolerance or obesity is compounded by overexpression of PTP1B in more than one insulin responsive tissue or by co- overexpression of another tyrosine phosphatase in addition to PTP1B in a single insulin responsive tissue. To "mimic" the overexpression of PTPs in obese humans, we will breed together transgenic mice made in aim one to create compound transgenics overexpressing PTPs in a combination of muscle, fat and liver. 3) To determine which tissue is responsible for the insulin sensitivity and leanness in PTP1B knockout mice by reconstituting PTP1B expression in muscle, liver or adipose tissue individually. This will be achieved by breeding each of the tissue-specific transgenic lines made in aim one with our PTP1B knockout mice. 4) To determine whether PTP1B deficiency can "cure" the severe insulin resistance or diabetes present in mice which are compound heterozygotes for knockout of the insulin receptor and insulin receptor substrate 1. These studies will lead to a better understanding of the mechanisms for regulation of glucose homeostasis and will elucidate the role of protein tyrosine phosphatases in the pathogenesis of insulin resistance that is associated with obesity and type 2 diabetes. Our goal is to find new therapeutic targets to reduce insulin resistance and prevent or ameliorate type 2 diabetes.